Editors’ Note: Malaria causes over 200 million new infections annually. Each year, more than 600,000 people die from the disease. The WHO estimates that an African child dies every minute from malaria. There has been progress, however. In April, the U.N. reported that malaria rates for children in Africa are down by half. Still, there is much to be done to prevent new outbreaks and provide better treatment options.
Albert Einstein College of Medicine of Yeshiva University’s Dr. Johanna Daily studies Plasmodium falciparum, the most deadly of the five malaria species that cause human disease, and the molecular mechanisms responsible for the range of disease outcomes that occur during infection. Specifically, she and her team are trying to explain what causes cerebral malaria, a severe form of the disease that causes a deep and often deadly coma, particularly in children. Dr. Daily is associate professor of medicine and of microbiology & immunology.
The Doctor’s Tablet blog spoke with her about the disease and her research. Science media relations manager Kim Newman contributed to this piece.
What should we know about malaria?
There are several types of malaria parasite species, and my lab studies Plasmodium falciparum, which is responsible for the vast majority of malaria-related fatalities. Another species, Plasmodium vivax, is slightly more prevalent worldwide, but rarely causes fatality. Knowing which type of malaria your patient has will determine the prognosis and need for hospitalization and dictate the type of antimalarial therapy that should be used. Malaria can be prevented by taking antimalarial prophylaxis, and knowledge of the type of malaria species present in the regions that will be visited is needed to select the correct drug.
After a mosquito transmits the parasite, it travels to the liver, where it silently replicates. The parasite can persist in the liver for weeks or months or years; typically in P. falciparum, it emerges to infect red cells and causes an illness within weeks, whereas vivax and other species can cause illness months after travel. P. falciparum readily emerges, but could emerge within a period of up to a year, and P. vivax even years later.
This is why it’s so important to rule out malaria if a febrile patient returns from an endemic area, even if it is weeks or months after he or she has returned. Another major point is that symptoms of malaria are completely nonspecific and could include, for example, fever, cough and GI symptoms, and thus all febrile patients who have traveled to a region where malaria is endemic need malaria diagnostic tests.
How widespread is malaria?
Malaria transmission continues to decrease worldwide due to malaria control programs, particularly under the leadership of the Gates Foundation. The numbers have decreased in Africa, where P. falciparum is prevalent and 90 percent of malaria-related deaths occur. The number of countries that have achieved eradication continues to increase. However, there are some regions with ecological attributes that make vector and malaria-control programs challenging, such as Malawi, parts of Kenya and other East African nations, and often this is linked to resource limitation that further impedes control programs.
What is the likelihood of developing malaria when taking a preventive medication?
Although malaria can result in morbidity, mortality and millions of infections annually, it is completely preventable. Any traveler who takes these drugs correctly will be completely protected. The prophylactic drugs we have are highly effective, and are routinely used for travelers. In endemic areas, prophylactic antimalarials are used for pregnant women and children under five in Africa, as infection in these populations results in more-severe complications.
I want to stress that when you take or prescribe an antimalarial, the entire course must be taken. We often see travelers who stop taking the drug when they return to the U.S. They need to extend the course after return, and in many cases when they prematurely stop taking the meds they end up becoming infected and develop illness. So it is very important to take the entire prescription as written and make this point very clear with your patients. Malaria is life-threatening for someone without any immunity.
What is cerebral malaria?
Cerebral malaria is a condition caused by P. falciparum. It is an unusual and severe complication that results in a coma. About 20 percent of the people who die from malaria each year have cerebral malaria. Any nonimmune person, meaning someone who hasn’t been exposed to malaria is at risk for this potentially deadly complication.
The associated mortality rate of cerebral malaria is 15 to 20 percent. It is fascinating to watch these children wake up from a deep coma, often within two or three days, and appear completely well, though 30 percent may develop behavioral problems or seizure disorders later on.
It is still unclear why these kids fall into a deep coma. Is it a local depletion of a brain nutrient or is it a toxin? Upon waking up, they immediately start playing and eating normally, so it appears to be a highly reversible mechanism, unlike, say, a stroke.
Tell me about your research.
I work with the Blantyre Malaria Project, a group of researchers who have a research ward devoted to studying these young children with coma. The ward is part of the Queen Elizabeth Teaching Hospital, a central hospital in Blantyre, Malawi, in Africa, so anytime children with coma and malaria enter the triage room they are offered enrollment into the study. When they are in the study, they get almost one-on-one nursing and intensive clinical care and everything about them is carefully studied, from fever curves to brain MRIs. This research program has also trained many Malawian healthcare workers and scientists, and this aspect is very exciting.
The first time I was there was in 1995, and I became extremely interested in studying why these children developed coma. Through collaboration we have had the opportunity to study host and parasite genetics, and more recently the blood metabolome in these children, to develop hypotheses regarding disease mechanisms. I have also been able to send students interested in tropical disease from my lab to work in Malawi, and we have had Malawian scientists visit Einstein to train and work at the bench here.
Our approach to studying the disease is to undertake an unbiased, comprehensive analysis of the physiology of these children through studying RNA and small molecules to find processes associated with cerebral malaria. Once we make disease associations, we and others can then explore the functional significance of specific genes or chemistry from these human studies in the experimental models of disease.
The disease association data have led us to examine many different aspects of human biology and genetics, and Einstein has been a great place to do this work as colleagues here have been very easy to collaborate with and able to provide in-depth expertise. The discovery process and the unraveling of this clinical puzzle have been very exciting.
One of my graduate students, Catherine Feintuch, has recently identified a neutrophil (a type of white blood cell) association with some of the severe consequences of cerebral malaria. Now that we have identified this association, we can take the next step to consider how these cells might mediate cerebral malaria and provide some clues to inhibit pathology.
Another member of my lab, Vasso Pappa, has identified a parasite gene associated with cerebral malaria, so part of her work is to express that protein and understand its role in parasite biology and how it may be involved in cerebral malaria. Finally, my medical student Sanchit Gupta is examining the blood metabolome in these children to identify small molecules that may be involved in coma and discover a biomarker for mortality that could identify children requiring more-intensive care to improve outcomes.
Do you think that the collective scientific understanding of malaria is expanding fast enough to stem this epidemic? What will it take for us to turn a corner?
Remember that malaria is completely preventable and completely treatable (though resistance is emerging in South East Asia to artemisinin, a key antimalarial drug). Thus programs that can provide infrastructure for vector control and accessible healthcare could make a big difference, but to date this has not happened, and practical solutions in this arena are needed.
